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Background NEC is a devastating neonatal disease characterized by intestinal necrosis. Hypoxia inducible factor-1α (HIF-1α) plays a critical role in cellular oxygen homeostasis. Here, we hypothesized that prolyl hydroxylase (PHD) inhibition, which stabilizes HIF-1α, protects against NEC by promoting intestinal endothelial cell proliferation and improving intestinal microvascular integrity via VEGF signaling. Methods To assess the role of PHD inhibition in a neonatal mouse NEC model, we administered DMOG or vehicle to pups prior to or during the NEC protocol, and determined mortality and incidence of severe intestinal injury. We assessed intestinal VEGF by Western blot and quantified endothelial cell and epithelial cell proliferation following immunofluorescence. Results DMOG decreased mortality and incidence of severe NEC, increased intestinal VEGF expression, and increased intestinal villus endothelial and epithelial cell proliferation in experimental NEC. Inhibiting VEGFR2 signaling eliminated DMOG’s protective effect on intestinal injury severity, survival, and endothelial cell proliferation while sparing DMOG’s protective effect on intestinal epithelial cell proliferation. Conclusion DMOG upregulates intestinal VEGF, promotes endothelial cell proliferation and protects against intestinal injury and mortality in experimental NEC in a VEGFR2-dependent manner. DMOG’s protective effect on the neonatal intestinal mucosa may be mediated via VEGFR-2 dependent improvement of the intestinal microvasculature.

Background Prolonged storage of transfused red blood cells (RBCs) is associated with hemolysis in healthy adults and inflammation in animal models. We aimed to determine whether storage duration affects markers of hemolysis (e.g., serum bilirubin, iron, and non-transferrin-bound iron (NTBI)) and inflammation (e.g., interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1) in transfused very low birth weight (VLBW) infants. Methods Blood samples from 23 independent transfusion events were collected by heel stick before and 2–6h after transfusion. Results Serum iron, total bilirubin, NTBI, and MCP-1 levels were significantly increased after transfusion of RBCs (P<0.05 for each comparison). The storage age of transfused RBCs positively correlated with increases in NTBI following transfusion (P<0.001; R2 = 0.44). No associations between storage duration and changes in the other analytes were observed. Conclusions Transfusion of RBCs into VLBW infants is associated with increased markers of hemolysis and the inflammatory chemokine MCP-1. RBC storage duration only correlated with increases in NTBI levels following transfusion. NTBI was only observed in healthy adults following 35 days of storage; however, this study suggests that VLBW infants are potentially more susceptible to producing this pathological form of iron, with increased levels observed after transfusion of only 20-day old RBCs.

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